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Sci Rep. 2017 May 15;7(1):1892. doi: 10.1038/s41598-017-01836-8.

Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine.

Author information

1
Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, Montevideo, Uruguay.
2
Immunobiology Department, Montevideo Faculty of Medicine, University of the Republic, Montevideo, Uruguay.
3
Ion Channels Laboratory, Biophysics Department, Montevideo Faculty of Medicine, University of the Republic, Montevideo, Uruguay.
4
Department of Cell Biology, School of Medicine of Ribeirão Preto, University of São Paulo, FMRP/USP, Ribeirão Preto, São Paulo, Brazil.
5
Laboratorio de Biotecnología, Facultad de Ingeniería-Universidad ORT Uruguay, Cuareim 1451, 11100, Montevideo, Uruguay.
6
Unit of Systemic Autoimmune Diseases, "C" Medical Clinic Prof. Dr. Juan Alonso Bao, Hospital of Clinics, Montevideo Faculty of Medicine, University of the Republic, Montevideo, Uruguay.
7
Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, Montevideo, Uruguay. mhill@pasteur.edu.uy.
8
Immunobiology Department, Montevideo Faculty of Medicine, University of the Republic, Montevideo, Uruguay. mhill@pasteur.edu.uy.

Abstract

Antimalarials have demonstrated beneficial effects in Systemic Lupus Erithematosus and Rheumatoid Arthritis. However, the mechanisms and the molecular players targeted by these drugs remain obscure. Although hydroxychloroquine (HCQ) is a known ion channel inhibitor, this property has not been linked to its anti-inflammatory effects. We aimed to study whether HCQ inhibits pro-inflammatory ion channels. Electrophysiology experiments demonstrated that HCQ inhibited Ca++-activated K+ conductance in THP-1 macrophages in a dose-dependent manner. In macrophages, ATP-induced K+ efflux plays a key role in activating the NLRP3 inflammasome. ATP-induced IL-1beta secretion was controlled by the KCa1.1 inhibitor iberiotoxin. NS1619 and NS309 (KCa1.1 and KCa3.1 activators respectively) induced the secretion of IL-1beta. This effect was inhibited by HCQ and also by iberiotoxin and clotrimazol (KCa3.1 inhibitor), arguing against off-target effect. In vitro, HCQ inhibited IL-1beta and caspase 1 activation induced by ATP in a dose-dependent manner. HCQ impaired K+ efflux induced by ATP. In vivo, HCQ inhibited caspase 1-dependent ATP-induced neutrophil recruitment. Our results show that HCQ inhibits Ca++-activated K+ channels. This effect may lead to impaired inflammasome activation. These results are the basis for i) a novel anti-inflammatory mechanism for HCQ and ii) a new strategy to target pro-rheumatic Ca++-activated K+ channels.

PMID:
28507328
PMCID:
PMC5432501
DOI:
10.1038/s41598-017-01836-8
[Indexed for MEDLINE]
Free PMC Article

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